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Mounting evidence indicates that Wnt signaling is relevant to pathophysiology of diverse mental illnesses including schizophrenia, bipolar disorder, and autism spectrum disorder. In the 35 years since Wnt ligands were first described, animal studies have richly explored how downstream Wnt signaling pathways affect an array of neurodevelopmental processes and how their disruption can lead to both neurological and behavioral phenotypes. Recently, human induced pluripotent stem cell (hiPSC) models have begun to contribute to this literature while pushing it in increasingly translational directions. Simultaneously, large-scale human genomic studies are providing evidence that sequence variation in Wnt signal pathway genes contributes to pathogenesis in several psychiatric disorders. This article reviews neurodevelopmental and postneurodevelopmental functions of Wnt signaling, highlighting mechanisms, whereby its disruption might contribute to psychiatric illness, and then reviews the most reliable recent genetic evidence supporting that mutations in Wnt pathway genes contribute to psychiatric illness. We are proponents of the notion that studies in animal and hiPSC models informed by the human genetic data combined with the deep knowledge base and tool kits generated over the last several decades of basic neurodevelopmental research will yield near-term tangible advances in neuropsychiatry.

We report a case of irritable bowel syndrome (IBS), diarrhea subtype, characterized by daily 'morning rush' and episodic acute exacerbations brought on by common IBS trigger foods including insoluble fiber, red wine and large/rich meals. The patient also had a history of migraine headaches, and a family history suggesting a common diathesis for both disorders. Given hypothesized contributions to IBS from dysregulation of the enteric serotonergic system, a trial of low-dose triptan medication was implemented in the context of the patient's known IBS triggers, with highly satisfactory results.

In mice, genetically engineered knockout of the Dapper Antagonist of Catenin-1 (Dact1) locus, which encodes a scaffold protein involved in Wnt signaling, leads to decreased excitatory input formation on dendrites of developing forebrain neurons. We have previously demonstrated this in both (excitatory, glutamatergic) pyramidal neurons of the hippocampus and in (inhibitory GABAergic) interneurons of the cortex. We have also demonstrated that knockout of the Dact1 locus leads to decreased dendrite complexity in cultured hippocampal pyramidal neurons, and to decreased spine formation on dendrites of forebrain pyramidal neurons in vitro and in vivo. Synapse phenotypes resulting from Dact1 loss in cultured cortical interneurons can be rescued by recombinant overexpression of the Dact1 binding partner, Dishevelled-1 (Dvl1), but not by recombinant expression of a constitutively active form of the small GTPase Rac1. This contrasts with dendrite spine phenotypes resulting from Dact1 loss in cultured hippocampal pyramidal neurons, which can be fully rescued by recombinant expression of activated Rac1. Taken together, these data suggest that in maturing forebrain neurons there are molecularly separate requirements for Dact1 in dendrite arborization/spine formation vs. synaptogenesis. Here, we show that the developmental requirement for Dact1 during dendrite arborization, which we previously demonstrated only in hippocampal pyramidal neurons, is also present in cortical interneurons, and we discuss mechanistic implications of this finding. © 2013 Landes Bioscience.

The planar cell polarity (PCP) pathway is a conserved non-canonical (β-catenin-independent) branch of Wnt signaling crucial to embryogenesis, during which it regulates cell polarity and polarized cell movements. Disruption of PCP components in mice, including Vangl2 and Dact1, results in defective neural tube closure and other developmental defects. Here, we show that Sestd1 is a novel binding partner of Vangl2 and Dact1. The Sestd1-Dact1 interface is formed by circumscribed regions of Sestd1 (the carboxyl-terminal region) and Dact1 (the amino-terminal region). Remarkably, we show that loss of Sestd1 precisely phenocopies loss of Dact1 during embryogenesis in mice, leading to a spectrum of birth malformations, including neural tube defects, a shortened and/or curly tail, no genital tubercle, blind-ended colons, hydronephrotic kidneys, and no bladder. Moreover, as with Dact1, a knock-out mutation at the Sestd1 locus exhibits reciprocal genetic rescue interactions during development with a semidominant mutation at the Vangl2 locus. Consistent with this, examination of Wnt pathway activities in Sestd1 mutant mouse embryonic tissue reveals disrupted PCP pathway biochemistry similar to that characterized in Dact1 mutant embryos. The Sestd1 protein is a divergent member of the Trio family of GTPase regulatory proteins that lacks a guanine nucleotide exchange factor domain. Nonetheless, in cell-based assays the Sestd1-Dact1 interaction can induce Rho GTPase activation. Together, our data indicate that Sestd1 cooperates with Dact1 in Vangl2 regulation and in the PCP pathway during mammalian embryonic development. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Members of the Wnt family of secreted signaling proteins influence many aspects of neural development and function. Wnts are required from neural induction and axis formation to axon guidance and synapse development, and even help modulate synapse activity. Wnt proteins activate a variety of downstream signaling pathways and can induce a similar variety of cellular responses, including gene transcription changes and cytoskeletal rearrangements. This review provides an introduction to Wnt signaling pathways and discusses current research on their roles in vertebrate neural development and function. © 2012 Springer Science+Business Media, LLC.